Bepirovirsen

Bepirovirsen is an antisense oligonucleotide, not a peptide. It is a single-stranded, chemically modified nucleic acid with a 2'-O-methoxyethyl gapmer design, discovered by Ionis Pharmaceuticals and licensed to GSK for clinical development under the code GSK3228836. It is included in this catalogue as a research compound of interest in chronic hepatitis B, but its chemistry and pharmacology differ fundamentally from peptides.

Bepirovirsen is not approved by the FDA or EMA and is in phase 3 clinical research. Chronic hepatitis B virus infection is difficult to resolve because the viral genome persists as covalently closed circular DNA in liver cells, and current antiviral agents suppress replication without eliminating viral antigens. A key research endpoint is sustained loss of hepatitis B surface antigen after an intervention ends. The phase 2b B-Clear study, published in 2022, reported surface antigen loss in a subset of participants, particularly those with lower baseline antigen levels, prompting the B-Well phase 3 programme. Research questions include durability, predictors of response and the immune contribution to its effects.

Bepirovirsen is designed to hybridise to a conserved sequence shared by all hepatitis B virus RNA transcripts, including pregenomic RNA and the messenger RNAs encoding viral proteins. Its central DNA gap, flanked by 2'-O-methoxyethyl-modified wings, recruits ribonuclease H1, which cleaves the RNA strand of the duplex and degrades the viral transcript. This reduces production of hepatitis B surface antigen and other viral proteins. Unlike GalNAc-conjugated oligonucleotides, bepirovirsen is unconjugated, which may allow uptake by non-hepatocyte cells. Studies have proposed an additional immunostimulatory component, possibly involving Toll-like receptor 8, that could contribute to antigen loss.